Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation and can cause sudden death.
Though various antiarrythmic agents are now available on the market, those having both satisfactory effects and high safety, have not been obtained. For example, antiarrythmic agents of Class I according to the classification of Vaughan-Williams which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (V.sub.max) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
A number of antiarrhythmic agents have been reported in the literature, such as those disclosed in:
(1) EP 397,121-A, (2) EP 300,908-A, (3) EP 307,121, PA1 (4) U.S. Pat. No. 4,629,739, (5) U.S. Pat. No. 4,544,654, (6) U.S. Pat. No. 4,788,196, PA1 (7) EP application 88302597.5, PA1 (8) EP application 88302598.3, PA1 (9) EP application 88302270.9, PA1 (10) EP application 88302600.7, PA1 (11) EP application 88302599.1, PA1 (12) EP application 88300962.3, PA1 (13) EP application 235,752, PA1 (14) DE 3633977-A1, PA1 (15) U.S. Pat. No. 4,804,662, PA1 (16) U.S. Pat. No. 4,797,401, PA1 (17) U.S. Pat. No. 4,806,555, PA1 (18) U.S. Pat. No. 4,806,536. PA1 X is O, S, or CH.sub.2 ; PA1 Y is C or O; with the proviso that, PA1 If Y is O, then R.sup.5 and R.sup.6 are absent and X is CH.sub.2 ; PA1 If X is O or S, then Y is C; PA1 R.sup.1 is H.sub.3 CSO.sub.2 NH--, H.sub.3 CO--, AlkylSO.sub.2 --, AlkylCONH--or NO.sub.2 --; PA1 R.sup.2 is --H, --OCH.sub.3 or Alkyl; PA1 R.sup.3 and R.sup.4 taken together are=O, or R.sup.3 is H and R.sup.4 is H, --OH, PA1 --NHCOCH.sub.3, --NHCOCH.sub.3 SO.sub.2 Phenyl, --NHCOCH.sub.3 SO.sub.2 Alkyl, PA1 NHCOCH.sub.2 SPhenyl, NHCOCH.sub.2 SAlkyl, --NHCOC(CH.sub.3).sub.2 OH or NHSO.sub.2 Alkyl; PA1 R.sup.5 and R.sup.6 are independently H, C.sub.1 -C.sub.6 Alkyl, or when taken together are PA1 --(CH.sub.2)n--, where n is 2-5; or =CH.sub.2 R.sup.7 is ##STR3## And R8 is --H --CH.sub.3, --OH, --CN, --O--C1--C6--alkyl, --NHCOAlkyl, --NHSO.sub.2 Alkyl, or --SO.sub.2 Alkyl; are Class Ill antiarrhythmic agents. PA1 or a pharmaceutically acceptable salt, hydrate, crystal form, enantiomer, diastereomer or mixtures thereof, wherein; PA1 X is O, S, or CH.sub.2 ; PA1 Y is C or O; with the proviso that, PA1 If Y is O, then R.sup.5 and R.sup.6 are absent and X is CH.sub.2 ; PA1 If X is O or S, then Y is C; PA1 R.sup.1 is H.sub.3 CSO.sub.2 NH--, H.sub.3 CO--, AlkylSO.sub.2 --, AlkylCONH-- or NO.sub.2 --; PA1 R.sup.2 is --H, --OCH.sub.3 or Alkyl; PA1 R.sup.3 and R.sup.4 taken together are=O, or R.sup.3 is H and R.sup.4 is H, --OH, PA1 --NHCOCH .sub.3, --NHCOCH.sub.3 SO.sub.2 Phenyl, --NHCOCH.sub.3 SO.sub.2 Alkyl, PA1 NHCOCH.sub.2 SPhenyl, NHCOCH.sub.2 SAlkyl, --NHCOC(CH.sub.3).sub.2 OH or PA1 NHSO.sub.2 Alkyl; PA1 R.sup.5 and R.sup.6 are independently H, C.sub.1 -C.sub.6 Alkyl, or when taken together are --(CH.sub.2)n--,where n is 2-5; or=CH.sub.2 PA1 R.sup.7 is ##STR5## And R8 is --H --CH.sub.3, --OH, --CN, --O--C1-C6--alkyl, --NHCOAlkyl, --NHSO.sub.2 Alkyl, or --SO.sub.2 Alkyl; are Class III antiarrhythmic agents.
Compounds of similar structure are found in Japanese patent publication 88-63533-B of Daiichi Pharmaceutical Co.; J. Med. Chem., 19, 1315 (1976) by Bauer et al; Iorio et al in Il. Farmaco-Ed Sci., 32, 212-219 (1977): Houlihan et al, U.S. Pat. No. 3,686,186; Davis et al, U.S. Pat. No. 4,420,485; Kealey, U.S. Pat. No. 4,810,792; Parham et al, J. Org. Chem., 41, 2629 (1976). None of the compounds disclosed in the foregoing references are alleged to have antiarrhythmic activity.
Now with the present invention, there is provided as antiarrhythmic agents new compounds with an increased degree of activity.